Alicia Morgans: Hi, this is Alicia Morgans, GU medical oncologist and Associate Professor of Medicine at Northwestern University. I am so excited to have here with me today, a friend and colleague, Dr. Fred Saad, who is a Professor and Chairman of Urology at the University of Montreal Hospital Centre in Montreal, Canada. Thank you so much for being here with us today.

Fred Saad: Always a pleasure, Alicia.

Alicia Morgans: Wonderful. We wanted to talk a little bit today about the updated data on PROSPER. You were one of the investigators on this study, which is really an international Phase III trial that led to the approval of enzalutamide in the nonmetastatic castration-resistant prostate cancer setting. And the updated data really tells us that this drug helps not just with metastasis-free survival, but has implications in terms of overall survival. Can you tell us a little bit about that, please?

Fred Saad: Yeah, so I'm sure everybody knows, it was published already, almost two years ago. Looking at its effect on delaying metastases, the MFS, which was the primary endpoint. It was clearly met and surpassed what we expected. Twenty-two-month improvement, a 71% delay in metastases, but the question always remained, how relevant is delaying metastases on the actual survival of patients? Because obviously if you start that early, it's more costly, you're increasing the cost, you're starting earlier and we never really had the proof that metastases first survival turns out to improve overall survival. And that's a really high bar because when you start that early, you've got so much opportunity to treat the placebo arm and make them do well. And, we might not have seen any survival advantage, especially that we see an mCRPC that when you've got an opportunity to really treat the placebo arm, those overall survival advantages were modest, three to four months.

I think we were all pleasantly surprised for our patients that we actually improved survival by almost one year. We went from in the study, it was 67 months survival, and is has mature data because it was followed when we reached the medium. Sixty-seven months for patients who started on enzalutamide in the nmCRPC state, versus 56 months in the patients that were very well treated on the placebo arm when they became metastatic. There are two things I think I take from that. Starting early really makes a difference for patients because that basically extra year or year and a half of therapy lead to almost a year of extra survival. That's almost a threefold increased chance of survival than waiting for mCRPC. I think hopefully people now are going to be convinced that earlier really does make a difference.

Alicia Morgans: I think that that is the main message that I take from it, too. Certainly is one of the most important things when we're trying to counsel our patients, although metastasis-free survival is also very important to them as is quality of life. But what I think is so important is that this data, as do the other two studies of androgen receptor antagonists in this nonmetastatic CRPC setting, really suggests that the earlier your treatments, the bigger bang for your buck. And I think you mentioned this on a conversation that we had maybe a year ago, you may not be able to make up for that lost time, which is what this suggests. What percentage of patients, or approximately what percentage of patients were actually treated in the control arm with active therapies? Because that's really so important as we think about this. If those patients did receive any therapy, first of all, that would be criminal. But secondly, that would suggest that any treatment's better than no treatment, but these patients received treatments.

Fred Saad: Oh yeah. The vast majority received treatment. Actually, if you take the whole group of placebo patients, 65% received subsequent therapy and then there's a large percentage that actually crossed over because when the MFS data came out, we unblinded the patients and the patients who still hadn't developed metastases or offered enzalutamide and obviously the vast majority accepted to go onto the active agent arm. And regardless of that, we still see this overall survival advantage. I think it really does exactly what you're saying. We don't catch up, even if you're looking for metastasis to start as early as possible as we did here because patients actually got subsequent treatment at 19 months of starting the placebo arm. Basically only a couple of months after they actually became metastatic. There was very little delay. Most of the patients were actually oligometastatic. And in the real world, we don't image every four months. These patients were followed extremely well. There was all the opportunity to treat early, but it didn't make up for treating upfront when you're nonmetastatic CRPC with high-risk features like rapid doubling time.

Alicia Morgans: I really want to emphasize that, that these patients were followed extremely closely to identify metastases. Probably in most patients' cases, this was not a symptomatic detection of metastasis. This wasn't "my PSA has doubled for several months and now finally you're imaging me" kind of metastasis. This was very structured, very standardized, and not necessarily what we would do in clinical practice. Much more closely followed and still, this approach led to nearly a year of improvement in overall survival.

Fred Saad: And what's really nice is exactly what you mentioned. This is not a fluke finding of one drug. All three showed the same thing. Clearly, earlier clearly is better. Many of us have been saying that from the time of 301 and 302 and PREVAIL and all point to that direction, but it was subgroups analysis, getting a sense that earlier did better. But now I think we really have the proof, patients who are CRPC, rapidly rising PSA have to be taken seriously, very much like the metastatic hormone-sensitive patient needs to be taken seriously.

Alicia Morgans: Because, as you're mentioning metastatic hormone-sensitive, these patients are essentially metastatic CRPC. We call them nonmetastatic because we can't detect their metastases by our conventional imaging. Interestingly, these patients, if imaged with more sensitive approaches like PSMA, predominantly, nearly all would demonstrate areas of metastatic disease. And the nonmetastatic name came from a need to differentiate between the clearly metastatic and we didn't know what kind of imaging we would ultimately have. But this is really a very low volume metastatic setting. And how does imaging come into play in your practice? I've heard people say, "Well, I'm not going to treat them because when I get their PSMA, I'm actually going to see that they're metastatic. And that just, then how do I apply these studies in that setting?"

Fred Saad: Yeah. That's a point that comes up often and it's a fair point. If we image them and like you said, we actually looked at a cohort of patients, 200 high-risk and mCRPC and 98% had something that showed up on PSMA. The question is, is that a good use of PSMA? We find something, does that mean that we're going to do radiation therapy surgery? What was the use? These patients need systemic therapy. They have a bad biology. Targeting metastatic sites with radiation or surgery is not going to likely help the patient. But if you do it in a patient with a slowly rising PSA that you think maybe they don't need systemic therapy because their doubling time is 18 or 24 months, then PSMA might be actually useful. In our center, we've actually put guidelines for using PSMA in a rational manner. And a high-risk nmCRPC is a contraindication for PSMA. We don't think it's a good use of resources.

Alicia Morgans: And it's also not a good use of the data because we have level one evidence, Phase III trials, actually three with a similar approach that suggests not only a metastasis-free survival benefit but an overall survival benefit. And we do not actually have survival data for things like SBRT to a single metastatic lesion. And all of the thoughts that we have about oligometastatic disease at this point are hypotheses that we hope will be born out with this targeted approach in addition though, I think in most cases, to at least some duration of systemic therapy. We just, we don't know the answers yet, but we do know that these drugs work. And so it's important for us to offer those to our patients, I think. And I appreciate your perspective. And it sounds like Canada is very rational as always with their use of their imaging.

Fred Saad: We have no choice. We have to be rational with our use of imaging, therapeutics. When Canada accepts new drugs, it's really based on very high-level evidence because we have universal health care so patients are going to get the drugs for free and we have to make sure we're making the best use of resources and funds.

Another minor thing is that we had questions whether patients with a PSA doubling time of less than six months are the only ones that would benefit. And what was reassuring is that even in survival, even the ones between six and 10 months do get a survival benefit. You don't need to super select patients. If your doubling time is less than 10 months, all these patients are likely to be harmed by the disease and likely to benefit even in terms of survival from being treated early.

Alicia Morgans: Well, thank you so much for walking us through this. And thank you for yet again, participating in the field's high-level knowledge, as you said. You've participated in yet another Phase III, really helped us understand how we can take better care of our patients. In this instance, in the nonmetastatic CRPC setting and in many other instances that we've talked about in the past. Thank you so much for your time and your contributions. We really appreciate it, Dr. Saad.

Fred Saad: It's a pleasure. Always fun.